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2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 179 ± 181
179
Lofexidine and desipramine: Interaction results in breakthrough opioid withdrawal symptoms 1
FRANCIS KEANEY , HELEN 2 3 CRIMLISK AND JENNIFER BEARN
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
1
2
Honorary Specialist Registrar, Senior 3 Registrar and Consultant Psychiatrist in Addiction/Honorary Senior Lecturer, National Addiction Centre (Institute of Psychiatry, King’s College London), Bethlem Royal Hospital, UK.
A patient was receiving treatment for concurrent opioid and stimulant dependency. When desipramine was added to his lofexidine regimen for treatment of stimulant withdrawal, there was an exacerbation of opioid withdrawal symptoms. With the increasing use of lofexidine for opioid withdrawal, clinicians need to be aware of the potential for interactions with tricyclic antidepressants in the treatment of concomitant stimulant users. (Int J Psych Clin Pract 2002; 6: 179 ± 181)
Correspondence Address F Keaney, National Addiction Centre, Addiction Sciences Building, 4 Windsor Walk, London SE5 8AF, UK. Tel: +44 (0) 20 7848 0747 Fax: +44 (0) 20 7701 8454
Received 29 June 2001; revised 25 May 2001; accepted for publication 10 October 2001
Keywords lofexidine desipramine drug-interaction opioid withdrawal
INTRODUCTION
R
esearch into the addictions has traditionally focussed on the treatment of single-drug dependency. Lofexidine, an alpha-2 agonist related to the antihypertensive agent clonidine, has been shown to be as effective as methadone in the treatment of opioid 1 detoxification. The tricyclic antidepressant agent desipramine has been demonstrated to be of benefit in treating the symptoms of withdrawal from stimulants 2 such as cocaine or amphetamines. However, drug users seeking treatment often abuse a number of substances simultaneously, and so there is a potential risk that these treatments may interact. Here we report the case of a man who was treated for concurrent opioid and stimulant dependency, in which there was a clinically significant interaction between lofexidine and desipramine. There is a well-documented interaction between clonidine and the tricyclic antidepressants, resulting in the loss of the antihypertensive effect of the former. This is thought to be related to inhibition of noradrenaline uptake or competition at central alpha-2 receptors. In this patient, there was an exacerbation of opioid withdrawal symptoms when desipramine was added to his lofexidine withdrawal regimen.
CASE REPORT A 31-year-old man was admitted to a dedicated inpatient drug detoxification unit for his polydrug dependency. In this unit there is constant supervision with close clinical observation. There is no access to any non-prescribed medications and there is regular urine testing for illicit drugs. 7 8 He fulfilled DSM-IV and ICD-10 criteria for amphetamine, opioid and alcohol dependence. He had a history of drug misuse since his early teens, starting with amphetamine at 13 years and opioids at 23. He had had no previous successful drug detoxification treatment. At the time of admission, he was taking 25 mg methadone orally and 0.25 g heroin intravenously daily. In addition he used 0.5 ± 1 g amphetamine intravenously 3 ± 4 times a week and drank 4 ± 6 cans of 9% (ABV) beer most days. There was no significant past medical or psychiatric history and his mental state on admission was normal with regards to speech, mood, affect and thoughts. He was stabilized on methadone over days 1 ± 3 at a dose of 60 mg per day, and alcohol withdrawal symptoms were controlled with 60 mg diazepam per day. Severity of opioid withdrawal was monitored with the Short Opiate 3 Withdrawal Scale (SOWS). After a stabilization period of
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
180
F Keaney et al
3 days he opted for a lofexidine detoxification regimen, which was given over 10 days (days 4 ± 13), as previously described by Bearn et al,1 and also with a 10-day diazepam detoxification for his alcohol dependency (see Figure 1). He suffered relatively few opioid withdrawal symptoms initially, but on day 8 he began to feel increasingly restless, anxious and depressed. These symptoms were thought to be indicative of stimulant withdrawal and so he was started on desipramine 75 mg daily. Over the next 48 h, his SOWS score increased substantially. In particular, he experienced marked insomnia, feelings of coldness, twitching, yawning and runny eyes. The desipramine was stopped after two doses and his withdrawal symptoms ameliorated over the following 24 h (Figure 2). His SOWS score decreased over the remainder of his detoxification programme, but unfortunately he discharged himself the day after the lofexidine regimen finished and relapsed soon afterwards.
DISCUSSION We acknowledge that it is difficult to distinguish the amphetamine withdrawal symptoms from other opioid withdrawal symptoms, given the multi-pharmacy involved. The stimulant withdrawal syndrome is best documented for cocaine, but amphetamine withdrawal is similar in nature.4 An initial `crash’ may occur 1 ± 4 days after abstinence, and is characterized by exhaustion and intense craving. Following this, a dysphoric state may develop with low 5 mood, anxiety and anhedonia. This state is thought to be related to depletion of dopamine and reduced dopaminergic neurotransmission; the clinical benefit of tricyclic antidepressants such as desipramine may be mediated through reversal of this depletion. Concurrent administration of the alpha-2 agonist lofexidine also reduces catecholamine neurotransmission and exacerbates stimulant withdrawal symptoms. The use of lofexidine as an alternative to methadone detoxification has a number of attractions: withdrawal symptoms abate earlier and it obviates the need for treatment with an opiate. Significant side-effects such as hypotension are uncommon. Since its introduction in the UK in 1992, the use of lofexidine has rapidly increased up to an estimated 20 000 6 opiate detoxifications in 1999. However, clinicians need to be aware of the potential interaction with tricyclic antidepressants, which may be of relevance in the treatment of concomitant stimulant users or in the management of patients with comorbid depressive disorders who are being treated with tricyclic antidepressants.
ACKNOWLEDGEMENTS Figure 1 M e d ic a tio n d o se s o f d ia z e p a m , m e th a d o n e a n d d e s ip ra m ine
We wish to thank Professor John Strang and Dr Alun Morinan for helpful comments on an earlier draft.
KEY POINTS
Figure 2 R e la tio ns h ip be tw e e n m e d ic a tio n re g im e n a n d S O W S sc o re s ( n o te d e s ip ra m in e c o m m e nc e s o n d a y 8 )
. Drug users seeking treatment often abuse a number of substances, so there is a potential risk that treatments for these substances may interact . Clinicians need to be aware that stimulant users undergoing an opioid detoxification may experience breakthrough opioid withdrawal symptoms if treated with tricyclic antidepressants
Lofexidine, desipramine and opioid withdrawal
181
REFERENCES
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
1. Bearn J, Gossop M, Strang J (1996) Randomised double-blind comparison of lofexidine and methadone in the in-patient treatment of opiate withdrawal. Drug Alcohol Depend 43: 87 ± 9. 2. Gawin FH, Kleber HD, Byck R et al (1989) Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46: 117 ± 21. 3. Gossop M (1990) The development of a Short Opiate Withdrawal Scale (SOWS). Addict Behav 15: 487 ± 90. 4. Lagos JA, Kosten TR (1994) Stimulant withdrawal. Addiction 89: 1477 ± 81. 5. Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch Gen Psychiatry 43: 107 ± 13.
6. Strang J, Bearn J, Gossop M (1999) Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addictions 8: 337 ± 48. 7. American Psychiatric Association (1996) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA. 8. World Health Organization (1992) International Classification of Diseases, 10th Revision (ICD-10). Geneva: WHO.
2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 179 ± 181
179
Lofexidine and desipramine: Interaction results in breakthrough opioid withdrawal symptoms 1
FRANCIS KEANEY , HELEN 2 3 CRIMLISK AND JENNIFER BEARN
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
1
2
Honorary Specialist Registrar, Senior 3 Registrar and Consultant Psychiatrist in Addiction/Honorary Senior Lecturer, National Addiction Centre (Institute of Psychiatry, King’s College London), Bethlem Royal Hospital, UK.
A patient was receiving treatment for concurrent opioid and stimulant dependency. When desipramine was added to his lofexidine regimen for treatment of stimulant withdrawal, there was an exacerbation of opioid withdrawal symptoms. With the increasing use of lofexidine for opioid withdrawal, clinicians need to be aware of the potential for interactions with tricyclic antidepressants in the treatment of concomitant stimulant users. (Int J Psych Clin Pract 2002; 6: 179 ± 181)
Correspondence Address F Keaney, National Addiction Centre, Addiction Sciences Building, 4 Windsor Walk, London SE5 8AF, UK. Tel: +44 (0) 20 7848 0747 Fax: +44 (0) 20 7701 8454
Received 29 June 2001; revised 25 May 2001; accepted for publication 10 October 2001
Keywords lofexidine desipramine drug-interaction opioid withdrawal
INTRODUCTION
R
esearch into the addictions has traditionally focussed on the treatment of single-drug dependency. Lofexidine, an alpha-2 agonist related to the antihypertensive agent clonidine, has been shown to be as effective as methadone in the treatment of opioid 1 detoxification. The tricyclic antidepressant agent desipramine has been demonstrated to be of benefit in treating the symptoms of withdrawal from stimulants 2 such as cocaine or amphetamines. However, drug users seeking treatment often abuse a number of substances simultaneously, and so there is a potential risk that these treatments may interact. Here we report the case of a man who was treated for concurrent opioid and stimulant dependency, in which there was a clinically significant interaction between lofexidine and desipramine. There is a well-documented interaction between clonidine and the tricyclic antidepressants, resulting in the loss of the antihypertensive effect of the former. This is thought to be related to inhibition of noradrenaline uptake or competition at central alpha-2 receptors. In this patient, there was an exacerbation of opioid withdrawal symptoms when desipramine was added to his lofexidine withdrawal regimen.
CASE REPORT A 31-year-old man was admitted to a dedicated inpatient drug detoxification unit for his polydrug dependency. In this unit there is constant supervision with close clinical observation. There is no access to any non-prescribed medications and there is regular urine testing for illicit drugs. 7 8 He fulfilled DSM-IV and ICD-10 criteria for amphetamine, opioid and alcohol dependence. He had a history of drug misuse since his early teens, starting with amphetamine at 13 years and opioids at 23. He had had no previous successful drug detoxification treatment. At the time of admission, he was taking 25 mg methadone orally and 0.25 g heroin intravenously daily. In addition he used 0.5 ± 1 g amphetamine intravenously 3 ± 4 times a week and drank 4 ± 6 cans of 9% (ABV) beer most days. There was no significant past medical or psychiatric history and his mental state on admission was normal with regards to speech, mood, affect and thoughts. He was stabilized on methadone over days 1 ± 3 at a dose of 60 mg per day, and alcohol withdrawal symptoms were controlled with 60 mg diazepam per day. Severity of opioid withdrawal was monitored with the Short Opiate 3 Withdrawal Scale (SOWS). After a stabilization period of
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
180
F Keaney et al
3 days he opted for a lofexidine detoxification regimen, which was given over 10 days (days 4 ± 13), as previously described by Bearn et al,1 and also with a 10-day diazepam detoxification for his alcohol dependency (see Figure 1). He suffered relatively few opioid withdrawal symptoms initially, but on day 8 he began to feel increasingly restless, anxious and depressed. These symptoms were thought to be indicative of stimulant withdrawal and so he was started on desipramine 75 mg daily. Over the next 48 h, his SOWS score increased substantially. In particular, he experienced marked insomnia, feelings of coldness, twitching, yawning and runny eyes. The desipramine was stopped after two doses and his withdrawal symptoms ameliorated over the following 24 h (Figure 2). His SOWS score decreased over the remainder of his detoxification programme, but unfortunately he discharged himself the day after the lofexidine regimen finished and relapsed soon afterwards.
DISCUSSION We acknowledge that it is difficult to distinguish the amphetamine withdrawal symptoms from other opioid withdrawal symptoms, given the multi-pharmacy involved. The stimulant withdrawal syndrome is best documented for cocaine, but amphetamine withdrawal is similar in nature.4 An initial `crash’ may occur 1 ± 4 days after abstinence, and is characterized by exhaustion and intense craving. Following this, a dysphoric state may develop with low 5 mood, anxiety and anhedonia. This state is thought to be related to depletion of dopamine and reduced dopaminergic neurotransmission; the clinical benefit of tricyclic antidepressants such as desipramine may be mediated through reversal of this depletion. Concurrent administration of the alpha-2 agonist lofexidine also reduces catecholamine neurotransmission and exacerbates stimulant withdrawal symptoms. The use of lofexidine as an alternative to methadone detoxification has a number of attractions: withdrawal symptoms abate earlier and it obviates the need for treatment with an opiate. Significant side-effects such as hypotension are uncommon. Since its introduction in the UK in 1992, the use of lofexidine has rapidly increased up to an estimated 20 000 6 opiate detoxifications in 1999. However, clinicians need to be aware of the potential interaction with tricyclic antidepressants, which may be of relevance in the treatment of concomitant stimulant users or in the management of patients with comorbid depressive disorders who are being treated with tricyclic antidepressants.
ACKNOWLEDGEMENTS Figure 1 M e d ic a tio n d o se s o f d ia z e p a m , m e th a d o n e a n d d e s ip ra m ine
We wish to thank Professor John Strang and Dr Alun Morinan for helpful comments on an earlier draft.
KEY POINTS
Figure 2 R e la tio ns h ip be tw e e n m e d ic a tio n re g im e n a n d S O W S sc o re s ( n o te d e s ip ra m in e c o m m e nc e s o n d a y 8 )
. Drug users seeking treatment often abuse a number of substances, so there is a potential risk that treatments for these substances may interact . Clinicians need to be aware that stimulant users undergoing an opioid detoxification may experience breakthrough opioid withdrawal symptoms if treated with tricyclic antidepressants
Lofexidine, desipramine and opioid withdrawal
181
REFERENCES
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/31/14 For personal use only.
1. Bearn J, Gossop M, Strang J (1996) Randomised double-blind comparison of lofexidine and methadone in the in-patient treatment of opiate withdrawal. Drug Alcohol Depend 43: 87 ± 9. 2. Gawin FH, Kleber HD, Byck R et al (1989) Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46: 117 ± 21. 3. Gossop M (1990) The development of a Short Opiate Withdrawal Scale (SOWS). Addict Behav 15: 487 ± 90. 4. Lagos JA, Kosten TR (1994) Stimulant withdrawal. Addiction 89: 1477 ± 81. 5. Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch Gen Psychiatry 43: 107 ± 13.
6. Strang J, Bearn J, Gossop M (1999) Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addictions 8: 337 ± 48. 7. American Psychiatric Association (1996) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA. 8. World Health Organization (1992) International Classification of Diseases, 10th Revision (ICD-10). Geneva: WHO.
